Zilpaterol is a known adrenergic β-2 agonist corresponding in structure to Formula (I):
The IUPAC name for zilpaterol is 4,5,6,7-tetrahydro-7-hydroxy-6-(isopropylamino) imidazo[4,5,1-jk]-[1]benzazepin-2(1H)-one. The Chemical Abstracts name for zilpaterol is 4,5,6,7-tetrahydro-7-hydroxy-6-[(1-methyl-ethyl)amino]-imidazo[4,5,1-jk][1]benzazepin-2(1H)-one.
Zilpaterol hydrochloride is sold by Merck Animal Health, under the trademark ZILMAX®. It is approved in the United States for increased rate of weight gain, improved feed efficiency, and increased carcass leanness in cattle fed in confinement for slaughter during the last 20 to 40 days on feed. The approved inclusion rate of zilpaterol hydrochloride is 6.8 grams/ton (7.5 ppm) in feed. In U.S. Pat. No. 4,585,770, Fréchet et al. discuss compounds, such as zilpaterol, encompassed by a genus characterized as 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-j-k][1]-benzazepin-2-(1H)-one derivatives and acid addition salts thereof. Fréchet et al. state that such compounds may be used as an active ingredient for inducing antihypertensive and hypotensive activity in a warm-blooded animal.
In U.S. Pat. No. 4,900,735, Grandadam discusses a zootechnical composition comprising zilpaterol and acid addition salts thereof. Grandadam states that such a composition may be used in general to increase the weight of cattle, pigs, sheep, and poultry.
In U.S. Pat. Nos. 5,731,028 and 5,847,124, Chevremont et al. discuss crystallized anhydrous zilpaterol hydrochloride, and particularly crystallized anhydrous zilpaterol hydrochloride wherein less than 5% of the crystals have a size of less than 15 μm, and at least 95% of the crystals have a size of less than 250 μm. According to Chevremont et al., such crystals may be incorporated into animal feed to increase body weight and meat quality. Chevremont et al. provide methods for making such crystals, and discuss using the crystals to make animal premixes in which the crystals are secured to a corn cob support having a greater particle size. They also discuss monohydrate and trihydrate intermediates that can be useful in, for example, making the crystals.
In U.S. Pat. No. 7,207,289, Montgomery discusses methods for increasing beef production, reducing feed intake while maintaining beef production, and reducing incidences of liver abscess in cattle. These methods comprise administering a feed comprising an ionophore and macrolide antibiotic during an initial period, and then administering a feed comprising zilpaterol (including zilpaterol hydrochloride) with essentially no ionophore or macrolide antibiotic.
In WO 2008/006828, Miculka, et al. disclose zilpaterol enantiomers compositions and methods of making and using such compositions to increase rate of weight gain, improve feed efficiency and increase carcass leanness in livestock, poultry and fish. In WO 2008/092924, Alemna-Perea et al. disclose enantioselective synthesis of zilpaterol and intermediates.
Ricks et al., (Reciprocal Meat Conference Proceedings, Vol. 37, 1984) disclose broiler chickens when fed the beta-agonist Clenbuterol at 1 ppm for 18 days (28 to 46 days of age) showed performance improvements in average daily gain (ADG) and feed efficiency (FE) of 3.3% to 3.0% respectively, above controls.
Mersmann, (1998, Journal of Animal Science, 76:160-172) summarized previous literature regarding the feeding of beta agonists to mammals and birds and suggested that the magnitude of effect of feeding beta agonists for growth promotion in chickens was lower (˜2% improvement) compared to other species. Beta agonists disclosed were norepinephrine, epinephrine, cimeterol, ractopamine, L.664.969 and salbutmol. The explanation provided for this low response, and generally accepted by the industry, was that some species (e.g., broiler chickens) have been intensely selected for growth rate and therefore has less potential to increase growth because they are closer to the biological maximal growth rate.
Kheiri, et al. (African Journal of Biotechnology, 2011, Vol. 10(68), pp 15450-15455) discloses the effect of the beta agonist ractopamine as a growth promoter of broiler chickens. Three levels of ractopamine were fed to broiler chickens from 3 to 6 weeks of age, 0, 5 and 10 mg/kg). The results indicate that daily body weight gain, feed intake, and feed conversion were not significantly affected by the administration of ractopamine to broiler chickens.
Towhidi, et al. (The 3rd International Conference on Sustainable Agriculture for Developing Countries, Jul. 26-29, 2011, pg 210) disclose that zilpaterol supplementation of feed for Japanese quails resulted in improved feed conversion ratio but there was not a significant difference in weight gain, final body weight, feed intake and carcass, thigh, breast liver and carcass weight. Birds were fed at zilpaterol levels of 0, 0.2, 0.225, 0.25 mg/kg of live body weight for a 21 day feeding study with birds at 26 days of age.
Towhidi, et al. (The 3rd International Conference on Sustainable Agriculture for Developing Countries, Jul. 26-29, 2011, pg 211) disclose the improved feed efficiency of chickens feed zilpaterol in a skip a day manner. Birds were fed at zilpaterol levels of 0, 0.2, 0.25, 0.3 mg/kg of live body weight for a 20 day feeding trial beginning at 25 days of age.